Background Fatigue is one of the most complex and severely disabling symptoms in multiple sclerosis (MS). There is an absence of a clear definition of fatigue and Uttle consensus exists on its relationship to the other features of MS. The underlying pathophysiology of MS fatigue is unknown and there are no effective treatments. Fatigue has been thought of as difficult to define and usually considered to be multidimensional. These two points, however, immediately present a paradox for the measurement of fatigue, since the fundamental principles of measurement require both strict definition and unidimensionality. The central hypothesis was that the phenomenon of fatigue, as a symptom in multiple sclerosis, could be defined in a detailed and coherent way and could then be measured, in order to facilitate understanding of its pathophysiology. The hypothesis was proven and in doing so many questions regarding the fundamental nature of atigue in MS were answered. It also provided the basis from which to pose questions, in a logical manner, regarding the underlying pathophysiology of the symptom.